The C-terminal domain of the Bloom syndrome DNA helicase is essential for genomic stability

This report demonstrates that the N-terminal domain of BLM is responsible for localization of the protein to the nuclear bodies, while the C-terminal domain directs the protein to the nucleolus. Deletions of the N-terminal domain of BLM have little effect on sister chromatid exchange frequency and chromosome stability as compared to helicase and C-terminal mutations which can increase SCE frequency and chromosome abnormalities.The helicase activity and the C-terminal domain of BLM are critical for maintaining genomic stability as measured by the sister chromatid exchange assay. The localization of BLM into the nucleolus by the C-terminal domain appears to be more important to genomic stability than localization in the nuclear bodies.Bloom syndrome (BS) is a rare cancer-prone autosomal recessive disorder characterized by genomic instability, immunodeficiency, infertility and small stature [1,2]. BS cells have a distinctive genomic instability: a high frequency of sister chromatid exchange (SCEs) and quadriradial formation. BLM, the gene mutated in BS, encodes a DNA helicase (BLM) of the RecQ family [3]. BLM shares the most identity in the helicase domain to the mouse and Xenopus orthologs [4,5,6], to a predicted C. elegans protein CAB05609 [7], and to D. melanogaster dmBLM [8]. BLM can partially complement phenotypes of mutations in the S. cerevisiae SGS1 gene [9,10]. There are two published reports of BLM knock-out mice: one strategy used a single deletion allele and found that the homozygous null mutants are embryonic lethals [4]; the second strategy used two different deletion alleles and recovered full sized, fertile compound heterozygote mice with an elevated incidence of cancer [5]. The second mouse model was made with ES cells that have a high frequency of SCEs before injection and recapitulates the BS phenotypes more accurately.There are four other human genes in the RecQ family: RecQL / RecQl, WRN, RecQ4, RecQ5 [11,12]. WRN is the gene mutated in Werner synd